RNA Silences Mutant Genes

Dr. Phillip A. Sharp, a professor at Massachusetts Institute of Technology, is seen in his laboratory at the Center for Cancer Research at MIT in Cambridge, Mass., Wednesday, July 16, 2003. Sharp said the emerging field of RNA interference has changed his research. The process, discovered by scientists in recent years, uses double stranded RNA to silence genes, which could help quash the effects of destructive genes behind cancer and other diseases.

The biotechnology field is littered with the debris of would-be miracle cures.

These days, the buzz is building around a technology called "RNA interference," whose legions of fans insist this one is different and could dramatically alter our understanding of molecular biology.

They may be right.

Even cynical veterans of biotechnology's failures find it hard to overstate how rapidly the technology has been embraced. Scientists researching everything from cancer to crops are using RNA interference to silence genes, thereby creating drugs, gene-searching tools and even a new way of decaffeinating coffee.

"It has totally changed my research," said Phillip Sharp, a Nobel laureate in gene research at Massachusetts Institute of Technology and co-founder of a company using the technology to develop drugs that would treat cancer, hepatitis and other diseases.

Sharp began working with RNA interference four years ago, when few scientists were interested in the field. Now, thousands of them aim to capitalize on the role RNA plays in life, custom-designing small snippets of double-stranded RNA to silence specific genes. They're publishing papers, filing for patents and organizing scientific conferences dedicated solely to the topic. Even skittish venture capitalists are investing in the field.

RNA was originally viewed simply as a passive messenger that took DNA's recipe from the cell's nucleus and delivered it to protein-building machines called ribosomes.

But recent discoveries show that double-stranded RNA patrols the genome with the job of silencing mutant genes. These RNA, armed with destructive enzymes, mug the messenger RNA from bad genes before it can reach the ribosome.

A similar kill-the-messenger method is used in "antisense" research, which involves injecting synthetically created mirror images of the RNA messenger that spreads an illness. The mirror image forms a double-helix bond with the RNA, preventing it from delivering its message to the body's protein-building machinery.

But antisense researchers have had trouble tricking human cells into accepting the foreign genetic material. Scientists hope RNA interference, which exploits a natural phenomenon, will prove easier to deliver.

RNA interference research is rapidly evolving, and the phenomenon remains little-understood. But what is known is that these double-stranded snippets effectively silence targeted genes. And that makes the experts optimistic.

"Most forms of life utilize this mechanism," said Dr. Peter Rowley of the University of Rochester Medical Center.

Rowley uses RNA interference to stop production of telomerase, an enzyme thought to keep cancer cells from dying. He presented his work Tuesday at the annual meeting of the American Association of Cancer Research in Washington D.C.

RNA interference is already streamlining the time, energy and money gene hunters spend slogging through the human genome attempting to determine what each of our 35,000 genes actually does.

A gene's function can be determined by turning it off and seeing what happens to the plant or animal.

"I've never seen anything like it," said Garret Hampton, head of cancer research at the Genomics Institute of the Novartis Research Foundation in San Diego. "The field has moved so incredibly fast because it's clearly powerful and has applications."

Researchers can now study gene functions in roundworms over a matter of days instead of weeks, feeding them bacteria designed to produce RNA that silences specific genes. By contrast, it usually takes about six months to engineer a mouse with a knockout gene;Sharp says "this technology offers the possibility of doing that in weeks."

But the big game hunt is for "magic bullet" drugs.

Drug makers and researchers have long sought to create drugs that target bad cells while leaving healthy ones alone, hoping to rely less on dangerous, blunt treatments such as chemotherapy.

Now, investors are betting RNA interference will be a powerful tool in customizing drugs.

In April, one struggling biotechnology firm drew a cash infusion of $48 million from venture capitalists as the company announced it was shifting away from its previous research to focus on RNA interference. The venture capitalists now own a majority ofBoulder, Colo.-based Sirna Therapeutics Inc.

MIT's Sharp helped start Alnylam Pharmaceuticals in Cambridge, Mass., last year with $17 million in venture capital investment. The company merged this month with German competitor Ribopharma AG and received $24.6 million in new funding.

"If the technology can be made to work, there's a long list of diseases it can be applied to," said Sharp. "Such a highly promising approach is worth the investment."

Still, even Alnylam chief executive John Maraganore said much hard work remains before the field proves worthy of all the excitement.

"Beyond the hype, people have to be cautious," Maraganore said. "There are still hurdles to overcome."

How to deliver the custom-designed snippets of RNA into the body is still a mystery. Researchers also must figure out a way to make sure the inserted RNA attacks only its intended targets.

"There is always a fear that there will be unintended consequences," said Gregory Hannon, an oft-cited RNA interference expert at Cold Springs Harbor Laboratory who has published several major findings in prestigious journals such as Science and Nature. "But even with a few off-target effects, it is still going to be better than any drug currently available. I believe this is revolutionary."